Project Summary/Abstract: The Alzheimer Disease Sequencing Project (ADSP) seeks to identify new genomic variants contributing to increased risk for and protection from Alzheimer's Disease in multi-ethnic populations, and to identify new pathways for disease treatment and prevention. Whole genome and whole exome sequencing data (WGS and WES) are available from ADSP Discovery and Discovery-Extension Phases and WGS in diverse ethnic groups will be generated for the Follow-up Study (FUS). The investigators of this proposal have diverse but complementary expertise across the range of bioinformatics, applied statistics and methodological development, admixture and ethnic diversity, rare variant association, network modeling, preclinical validation of targets, and clinical expertise in AD and have been involved in the ADSP since its inception. Further they bring expertise on endophenotypes and additional WGS data through their role within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) and TOPMed (Trans-Omics for Precision Medicine) consortia. We now propose the following aims to meet ADSP goals. Aim 1: To fully characterize known AD loci and to identify novel protective and risk variants for AD by exploiting the full range of genetic variability revealed by WGS including single nucleotide polymorphisms, small insertion/deletions, and structural variants. Analyses will include expanded association analyses of AD and endophenotypes, identification of novel protective variants via carefully selected ?Wellderly? samples, and integration of findings across analyses. Aim 2: To leverage ethnically-diverse and admixed populations to identify novel variants for AD and endophenotypes. This will be achieved by estimating and accounting for global-scale population structure in association analyses across the three phases of ADSP. We additionally propose to perform admixture mapping in samples of admixed ancestry and to perform ethnic-specific analyses and trans-ethnic meta- analyses. Aim 2 analyses will be performed for AD, AD endophenotypes, and Wellderly status. Aim 3: To functionally characterize genes, gene networks, and systems, via bioinformatics and omics integrative analyses to identify putative therapeutic targets. The investigators will work closely with the Accelerating Medicines Partnership (AMP) projects. We propose to use a combination of bioinformatics tools and analysis of ?omics? data, including DNA methylation, gene expression, miRNA and metabolomics data within AMP and in the CHARGE cohorts to predict function of specific variants or groups of variants, to apply network approaches across gene sets, to utilize a systems approach to understand the ADSP sequencing data in the larger context of human biology and to identify putative therapeutic targets. Our proposal provides a comprehensive, integrated plan, which we will implement within the existing ADSP infrastructure and in coordination with ADSP investigators.